Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis.
Alleles
Animals
Body Weight
Cell Line, Tumor
Crosses, Genetic
Gene Deletion
Gene Knock-In Techniques
Genetic Variation
HEK293 Cells
Heterozygote
Homeostasis
Humans
Hypothalamus
/ metabolism
Leptin
/ metabolism
Male
Membrane Potentials
Mice
Mice, Transgenic
Mutation, Missense
Neurons
/ metabolism
Nuclear Receptor Coactivator 1
/ genetics
Obesity
/ genetics
Phenotype
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
12 04 2019
12 04 2019
Historique:
received:
26
09
2018
accepted:
21
01
2019
entrez:
14
4
2019
pubmed:
14
4
2019
medline:
10
5
2019
Statut:
epublish
Résumé
Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1
Identifiants
pubmed: 30979869
doi: 10.1038/s41467-019-08737-6
pii: 10.1038/s41467-019-08737-6
pmc: PMC6461669
doi:
Substances chimiques
Leptin
0
NCOA1 protein, human
EC 2.3.1.48
Ncoa1 protein, mouse
EC 2.3.1.48
Nuclear Receptor Coactivator 1
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1718Subventions
Organisme : NCI NIH HHS
ID : R01 CA193455
Pays : United States
Organisme : NIDDK NIH HHS
ID : P01 DK113954
Pays : United States
Organisme : British Heart Foundation
ID : RG/13/13/30194
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK101379
Pays : United States
Organisme : NIDDK NIH HHS
ID : P01 DK059820
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD007857
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114279
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK107008
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK117281
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK093587
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_12012/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R00 DK107008
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA112403
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00014/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/18/13/33946
Pays : United Kingdom
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